Bridged PROTAC, DNA-based PROTAC and hydrophobic tag technologies for targeted protein degradation

Proteolysis targeting chimeras (PROTACs) represent an important breakthrough in therapeutic discovery by leveraging the ubiquitin-proteasome system (UPS) to induce targeted protein degradation (TPD). Unlike conventional small-molecule inhibitors, PROTACs catalytically degrade target proteins, thereby abolishing all functions of target proteins. Over the past decade, PROTAC technology has demonstrated broad therapeutic utilities across diverse disease-relevant proteins and many PROTACs have progressed into clinical development. However, classical PROTACs rely on the availability of small-molecule binders for both proteins-of-interest (POIs) and E3 ligases, thus limiting the degradable proteome. To overcome these limitations, innovative strategies such as bridged PROTACs, DNA-based PROTACs, and hydrophobic tag-based degraders (HyTs) have been developed. Bridged PROTACs take advantage of endogenous protein-protein interactions to target the "undruggable" POIs or underexplored E3 ligases. DNA-based PROTACs use DNA oligonucleotides linked to E3 ligase ligands to degrade undruggable transcription factors (specifically termed TF-PROTAC), which lack small-molecule binding pockets and ligands. HyTs utilize a hydrophobic tag to potentially induce POI misfolding and subsequent degradation. HyTs, which have lower molecular weight than typical PROTACs, can be orally bioavailable. Collectively, these technologies expand the targetable proteome and significantly advance the TPD field.